The present invention is in the field of organic synthesis, and is specifically related to a process for electrophilic substitution on aromatic compounds.
The term electrophilic aromatic substitutions covers a broad class of reactions in which an electrophile is linked to an aromatic compound instead of a leaving group, which is generally a hydrogen atom. The electrophile may be a heteroatom, such as in the case of halogenation reactions. In acylation and alkylation reactions, a carbon side chain is introduced onto the aromatic ring.
The art teaches that the above mentioned reactions are catalyzed by certain Lewis acids. In the halogenation of some aromatic compounds, such as, for example, benzene, ferric halide or aluminum halide are typically employed as the catalytic reagent. In acylation and alkylation reactions (Friedel-Crafts and related processes), aluminum halide is accepted as the preferred catalyst. Other reagents known in the art for the catalysis of electrophilic aromatic substitutions are boron trifluoride or strong acids.
While aluminum chloride is considered to be a powerful catalyst for the purpose of electrophilic aromatic substitutions, a major drawback associated with its use is that it is not recyclable and cannot be employed in a subsequent reaction, since aluminum chloride undergoes hydrolysis, reacting violently with water to produce HCI. The production of wastes which are expensive to dispose of, leading to increases in the overall production costs, significantly impair the productivity of any industrial process employing said catalyst.
Another relevant synthetic problem is concerned with the orientation of electrophilic substitution on the aromatic ring. It is well known that if the substrate undergoing the reaction bears substituent groups, e.g. halogens, carbonyls or ether linkages, this will often strongly influence the pattern of a subsequent substitution, so that certain sites on the aromatic ring system will be preferred, and other sites will be disfavored. In many instances, however, it is desired to substitute at the disfavored positions, and therefore it would be useful to provide a means for substitution at these disfavored sites when necessary.
Four situations, which illustrate the foregoing drawbacks of the state of the art with respect to certain compounds of great industrial importance, are as follows:
1. 5-bromo-2-chloro-4-fluoroanisole (hereinafter 5-BCFA) is a compound useful as an intermediate in the synthesis of certain agrochemicals. The particular substitution pattern of 5-BCFA makes the synthesis of this compound (in preference to the corresponding 6-bromo compound) a challenge. Although means of preparing 5-BCFA via multi-step synthesis are conceivable, such processes, like many multi-step syntheses, would be expensive to carry out on a large scale and would therefore not readily lend themselves to industrial exploitation.
For industrial use, a desirable preparation of 5-BCFA would involve direct bromination of 2-chloro-4-fluoroanisole (hereinafter xe2x80x9cCFAxe2x80x9d). JP 4-356438 A2 discloses the direct bromination of CFA, using sulfuric acid as the reaction medium. However, this process is reported to yield 27% of the desired 5-bromo isomer, after column chromatography. This method is not readily amenable to large scale industrial production.
2. 6-acetyl-2-methoxy naphthalene (6-AMN) is an intermediate in the synthesis of naproxen, an anti-inflmatory agent. One method for the production of 6-AMN involves a three-step process starting from 2-methoxy napthalene (neroline), comprising protection of neroline at the 1-position, acylation at the 6-position using AlCl3 as catalyst, and removal of the protecting group to yield 6-AMN. Such a process uses large amounts of AlCl3 and generates large amounts of waste; therefore alternatives to this process which use less reagent, generate fewer wastes, and involve fewer steps would be be beneficial.
3. An intermediate in the production of 3-phenoxy benzaldehyde, a compound used for the production of pyrethroids, is 3-bromobenzaldehyde. Processes currently used for this bromination involve massive amounts of aluminum chloride, which generate large amounts of aluminous wastes and increase production costs. An inexpensive, recyclable AlCl3 replacement would help lower costs and lessen the environmental impact.
4. 3-bromo-4fluorobenzaldehyde is a starting material for the synthesis of effective agrochemicals. It can be prepared by bromination of 4-fluorobenzaldehyde by using large amounts of aluminum chloride. This, again, involves the production of great masses of waste. As stated hereinbefore, recyclable alternatives to AlCl3 would help lower costs and lessen the environmental impact of this process.
Other attempts reported in the art with reference to electrophilic aromatic substitutions are directed to the alkylation of phenols or alkyl-substituted derivatives thereof ie., to the alkylation of aromatic substrates which are considered highly activated, and therefore, are expected to undergo the substitution without special difficulty. GB 1235240 and GB 1344965 disclose processes for the alkylation of phenols or alkyl-substituted phenols, using catalytic system comprising zinc bromide or zinc chloride and hydrogen bromide or hydrogen chloride. SU 235040 discloses the alkylation of substituted phenol, using zinc chloride, HCI and alkaline salts, and specifically NaCl, which is alleged to increase the reaction yield by 10 to 15%, at a high temperature.
Otherwise, aqueous solutions of zinc bromide are generally known in the art as completion fluids for oil drilling.
JP 62-148465 describes the bromination of Bisphenol S in an organic solvent at a temperature in the range between 10 to 50xc2x0 C., using hydrobromic acid solution, or a mixture of bromine and water, hydrogen peroxide and zinc halide. JP 62-48641 describes a corresponding process using Bisphenol A as the substrate.
It is an object of the invention to provide a simple and inexpensive process for electrophilic aromatic substitutions, in particular for halogenations, acylations and alkylations.
It is another object of the invention to provide such a process in which the principal reagent is of low toxicity and may be recycled, thereby reducing the amount of reagent required, reducing the amount of waste produced, and limiting the danger to man and the environment.
It is another purpose of the present invention to provide a process for electrophilic aromatic substitution in which the selectivity of the substitution towards a desired site on the aromatic ring system is improved with respect to presently known processes.
Other objects and advantages of the present invention will become apparent as the description proceeds.
The present invention provides a process for the electrophilic substitution of an aromatic compound, comprising contacting said aromatic compound, a precursor of the desired substituent and an aqueous reagent containing zinc halide, at an elevated temperature.
The preferred electrophilic aromatic substitution reactions according to the present invention are selected from among halogenation, acylation and alkylation reactions, provided that if the reaction is an alkylation, then the aqueous reagent contains zinc bromide, a bromide salt of an alkali metal or an alkaline earth metal, preferably LiBr, and an acid. By the term halogenation, particularly bromination and chlorination are intended.
It has been surprisingly found by the inventors, that an aqueous medium containing zinc halide, e.g., ZnBr2 and ZnCl2, which, as stated above, was previously known for use as completion fluids for oil drilling, may be applied as a recyclable reagent for a variety of electrophilic substitutions of aromatic compounds, at an elevated temperature, typically at a temperature above 50xc2x0 C., and preferably between 60 to 160xc2x0 C. Thus, an important feature of the present invention is the wide application of said aqueous reagent containing zinc halide as a primary medium for electrophilic aromatic substitutions, which can optionally be adapted with ease according to the requirements of the particular substitution intended. For example, when the electrophilic substitution is an alkylation reaction of aromatic compounds, the zinc halide present in said aqueous reagent is zinc bromide, together with an acid and a corresponding bromide salt of an alkali metal or an alkaline earth metal, which is preferably LiBr. The process according to the present invention is useful even for the substitution of strongly deactivated aromatic substrates, allowing convenient medium recycling without a significant decrease in the effectiveness of the catalytic medium, as well as improved conversion of the said aromatic substrate to the desired substituted derivative.